Amniotic Fluid Angiopoietin-1, Angiopoietin-2, and Soluble Receptor Tunica Interna Endothelial Cell Kinase-2 Levels and Regulation in Normal Pregnancy and Intraamniotic Inflammation-Induced Preterm Birth

作者：Buhimschi Catalin S^*; Bhandari Vineet; Dulay Antonette T; Thung Stephen; Abdel Razeq Sonya S; Rosenberg Victor; Han Christina S; Ali Unzila A; Zambrano Eduardo; Zhao Guomao; Funai Edmund F; Buhimschi Irina A

来源：Journal of Clinical Endocrinology & Metabolism, 2010, 95(7): 3428-3436.

DOI：10.1210/jc.2009-2829

Background: Angiopoietin-1 (Ang-1) and Ang-2 act selectively on endothelial cells by engaging the Tunica interna endothelial cell kinase-2 (Tie2) receptor. A soluble form of Tie2 (sTie2) blocks angiopoietin bioactivity.
Objective: The aim of the study was to characterize changes and expression patterns of Ang-1, Ang-2, and sTie2 in amniotic fluid (AF) and placenta during human pregnancy and intraamniotic inflammation (IAI)-induced preterm birth.
Design and Setting: We conducted a cross-sectional study at a tertiary university hospital.
Patients: AF levels of Ang-1, Ang-2, and sTie2 were evaluated in 176 women during second trimester (n = 40), third trimester (n = 37), and preterm labor (positive IAI, n = 50; negative IAI, n = 49). Placenta and cord blood of select women were analyzed.
Main Outcome Measures: Ang-1, Ang-2, sTie2, and IL-6 were evaluated by ELISA. Real-time PCR measured Ang-1, Ang-2, and Tie2 placental mRNA levels. Placenta was immunostained for Ang-1 and Ang-2. Placental explant cultures were stimulated with lipopolysaccharide, Pam3Cys, and modulators of protein synthesis/secretion (cycloheximide, monensin, and brefeldin A).
Results: In normal pregnancy, the levels and ratios of AF Ang-1, Ang-2, and sTie2 varied with gestational age (GA) (P < 0.001). PCR revealed corresponding changes in placental Ang-1 and Ang-2, but not Tie2, mRNA. IAI raised AF Ang-1, Ang-2, and sTie2 above the expected level for GA without affecting their placental mRNA. Ang-2 immunoreactivity appeared enhanced in areas of villous edema. AF Ang-2/Ang-1 ratio was an important determinant of cord blood IL-6 (P < 0.001). Ex-vivo, sTie2 release was increased by Golgi disrupting but not bacterial mimic agents.
Conclusions: Ang-1, Ang-2, and sTie2 are physiological constituents of AF that are GA and IAI regulated. Ang-2/Ang-1 ratio may play a role in modulating the fetal inflammatory response to IAI. Placental sTie2 shedding likely involves a Golgi-mediated mechanism. (J Clin Endocrinol Metab 95: 3428-3436, 2010)

• 出版日期2010-7